Pulmonary Pathophysiology Research Articles

Pulmonary Pathophysiology Following a Combined Burn and Smoke Inhalation Injury in Sheep

Journal Article Pulmonary Pathophysiology Following a Combined Burn and Smoke Inhalation Injury in Sheep Get access T. Van Dinter, Jr., BS, T. Van Dinter, Jr., BS 1University of Texas Medical Branch and Shriners Burns Institute, Galveston, TX Search for other works by this author on: Oxford Academic Google Scholar R. A. Cox, MS, R. A. Cox, MS 1University of Texas Medical Branch and Shriners Burns Institute, Galveston, TX Search for other works by this author on: Oxford Academic Google Scholar K. Murakami, MD, K. Murakami, MD 1University of Texas Medical Branch and Shriners Burns Institute, Galveston, TX Search for other works by this author on: Oxford Academic Google Scholar J. Katahira, MD, J. Katahira, MD 1University of Texas Medical Branch and Shriners Burns Institute, Galveston, TX Search for other works by this author on: Oxford Academic Google Scholar H. K. Hawkins, MD, PhD, H. K. Hawkins, MD, PhD 1University of Texas Medical Branch and Shriners Burns Institute, Galveston, TX Search for other works by this author on: Oxford Academic Google Scholar D. L. Traber, PhD D. L. Traber, PhD 1University of Texas Medical Branch and Shriners Burns Institute, Galveston, TX Search for other works by this author on: Oxford Academic Google Scholar The Journal of Burn Care & Rehabilitation, Volume 23, Issue suppl_2, March-April 2002, Page S121, https://doi.org/10.1097/00004630-200203002-00157 Published: 01 March 2002

Association between decreased pulmonary endothelial cell thrombomodulin and local fibrin deposition in pneumonia.

Thrombomodulin (TM) plays an important role in anticoagulation by forming a complex with thrombin, which subsequently activates protein C. TM is inactivated and downregulated by inflammatory cell mediators. This study examined whether bronchopneumonia is associated with changes in TM immunoreactivity, and whether a decrease in TM is accompanied by evidence of hypercoagulability, i.e. local deposition of fibrin. Double antibody staining for TM and fibrin was performed on lung tissue sections from patients who had died of pneumonia and from patients who had died rapidly, secondary to trauma. Inflammatory changes were assessed histologically and immunohistochemically using antibodies against interleukin-1alpha, tumor necrosis factor-alpha, and myeloperoxidase. Areas with bronchopneumonia exhibited markedly decreased endothelial TM staining of alveolar walls and small vessels. These changes were associated with prominent fibrin immunoreactivity. Some areas exhibited mild to moderate inflammation with little fibrin deposition and variable amounts of TM in adjacent vessels. This study is the first to relate changes of TM immunoreactivity levels to fibrin deposition in a human disease process. These data may have implications for pulmonary pathophysiology in patients with bronchopneumonia.

Pulmonary immunohistochemistry and serum levels of a surfactant-associated protein A in fatal drowning

To evaluate the immunohistochemical distribution and serum levels of a pulmonary surfactant-associated protein A (SP-A) in fatal drowning with regard to the pulmonary alveolar injury, 53 autopsy cases were investigated. SP-A was membranously or linearly demonstrated in varying intensities on the intra-alveolar interior surface and on the interface of the intra-alveolar effusion. A high score of intra-alveolar aggregates of SP-A was significantly more frequently observed in freshwater than saltwater drowning. The left/right ratios of cardiac blood SP-A level were significantly high both in fresh- and saltwater drowning, showing no relationship to aggregated SP-A scores. Immunohistochemical score and serum level of SP-A were independent of the lung weight or pleural effusion. These observations suggest a partial difference of pulmonary pathophysiology depending on the immersion medium in fatal drowning.

The treatment of acute respiratory failure in children: A historical examination of landmark advances

Over the last 2 centuries, our understanding of lung function and pulmonary pathophysiology has increased tremendously. Even in the 20th century, though, truly new developments have come at irregular intervals. The pace of advancement has been fitful, at times exhilarating, at other times frustrating. For example, after refinement of positive-pressure mechanical ventilation in the late 1960s, the mortality rate for acute respiratory failure in children appeared to remain unchanged for over 20 years. Now, recent investigations that have deepened our understanding of ventilator-associated lung injury have produced new treatment approaches and significant improvement in outcomes.

Airspace Surface Chemistry Mediates O3-Induced Lung Injury

Ozone (O3) produces diverse pulmonary pathophysiologies but with marked heterogeneities relative to species, age, anatomic site, disease, and exposure history. These pronounced susceptibility variations have remained largely undefined. We have postulated that interactions between inhaled O3 and the airspace surfaces appreciably govern the distribution and extent of lung injury. O3 displays unique absorption properties wherein chemical reaction with the epithelial lining fluid (ELF) maintains the net flux from the gas phase and couples O3 uptake with the generation of products that lead to cell injury. Diversities in respiratory tract geometry and interfacial physicochemical conditions leads to spatially heterogeneous rates of O3 flux into the ELF which combine with the local production of bioactive species to dictate the local dose. We have observed that both the uptake and distribution of acute epithelial injury is principally localized to the conducting airways. O3 preferentially reacts with ELF ascorbic (AH2) and uric acids (UA) although reaction with GSH and unsaturated fatty acids (UFA) occur to a lesser extent. UFA reactions may not generate sufficient bioactive materials to account for acute cell injury. Reactions with AH2 and GSH, but not UA or Trolox, form secondary oxidants that initiate oxidation of model membranes and in vitro cell damage. However, secondary oxidant production is antioxidant concentration-dependent with a hyperbolic-shaped dose/response curve. Acquisition of species-specific data characterizing the pharmacodynamics of ELF substrate turnover under both basal and exposure conditions are critical to further our understanding of how surface chemistry regulates the balance between quenching of inhaled O3 and conditions that promote production of bioactive/cytotoxic species and, therefore, biological outcomes.

Isoprostanes: an overview and putative roles in pulmonary pathophysiology

Isoprostanes are produced during peroxidation of membrane lipids by free radicals and reactive oxygen species. Initially, they were recognized as being valuable markers of oxidative stress, and in the past 10 years, dozens of disease states and experimental conditions with diverse etiologies have been shown to be associated with marked increases in urinary, plasma, and tissue levels of isoprostanes. However, they are not just mere markers; they evoke important biological responses on virtually every cell type found within the lung, and these responses exhibit compound-, tissue-, and species-related variations. In fact, the isoprostanes may mediate many of the features of the disease states for which they are used as indicators. In this review, I describe the chemistry, metabolism, and pharmacology of isoprostanes, with a particular emphasis on pulmonary cell types, and the possible roles of isoprostanes in pulmonary pathophysiology.

Pulmonary ventilation: dynamic MRI with inhalation of molecular oxygen

We have recently demonstrated a non-invasive technique to visualize pulmonary ventilation in humans with inhalation of molecular oxygen as a paramagnetic contrast agent. In the current study, T1 shortening of lung tissue by inhalation of oxygen was observed ( P<0.001). The T1 values of lung tissue were also correlated with arterial blood oxygen pressure (PaO 2) in a pig, resulting in excellent correlation ( r 2=0.997). Dynamic wash-in and wash-out MR ventilation images as well as dynamic wash-in wash-out signal intensity versus time curves were obtained. The mean wash-in decay constants were 26.8±10.5 s in the right lung, and 26.3±9.5 s in the left lung. The mean wash-out decay constants were 23.3±11.3 s in the right lung, and 20.8±10.5 s in the left lung. Dynamic assessment of pulmonary ventilation is feasible using oxygen-enhanced MR imaging, which could provide dynamic MR ventilation-perfusion imaging in combination with recently developed MR perfusion imaging technique, and thus a robust tool for the study of pulmonary physiology and pathophysiology.

Immune Complex Formation after Xenotransplantation: Evidence of Type III as well as Type II Immune Reactions Provide Clues to Pathophysiology

Rejection of renal and cardiac xenografts is initiated when natural antibodies of the recipient bind to donor endothelium, activating complement on the surface of endothelial cells. Pulmonary xenotransplants, however, reveal less evidence of antibody binding and complement activation and, in contrast to other xenografts, fare worse when the complement of the graft recipient is depleted. Accordingly, we asked whether distinct immunochemical reactions might occur after xenotransplantation of the lung and what implications such reactions might have for pulmonary pathophysiology. Analysis of serum from baboons after transplantation with porcine lungs revealed complexes containing baboon IgM and porcine von Willebrand factor. The baboon IgM in these complexes was specific for Galalpha1-3Gal. Immune complexes were also seen, albeit to a lesser extent, in the serum of kidney and heart xenotransplant recipients. Deposits of porcine von Willebrand factor and baboon C3 were detected in livers and spleens of transplanted baboons. These results indicate pulmonary xenotransplantation eventuates in formation of immune complexes and in the deposition of those complexes at distant sites. Immune complex formation could explain the peculiar fate of xenoreactive antibodies after pulmonary xenotransplantation and might contribute to the pathophysiology of the lung and systemic changes not previously considered a complication of xenotransplantation.

Measurement of Ventilation-Perfusion Ratio Using Multiple Inert Gas Elimination Technique in the Endotoxin-Induced Septic Rabbit

Background: Endotoxin is a complex lipopolysaccharide molecule situated within the outer membrane of Gram-negative bacteria. Sepsis and acute respiratory failure (ARDS) can be induced by endotoxin. In order to introduce and develop the experimental model of ARDS in sepsis, we induced sepsis with the endotoxin and investigated the change of respiratory pathophysiology during sepsis using a multiple inert gas elimination technique (MIGET). Methods: Ten New Zealand white rabbits were anesthetized and ventilated with a Harvard apparatus. In 5 rabbits, 2 mg/kg of lipopolysaccaride from E. coli was infused intravenously for 30 min (Toxin group). At 1, 2, 3, and 4 hours after endotoxin infusion, arterial blood gas, and hemodynamic profiles were checked. To perform the MIGET, six inert gases (SF6, krypton, desflurane, enflurane, diethyl ether, acetone) of widely varying solubility were infused peripherally and the excretion and retention data was determined from measurements of inert gas tensions in pulmonary arterial, systemic arterial blood samples and mixd expiratory gas sampling of pre and post septicemia using gas chromatography. We transformed and analysed the data into a V/Q distribution curve to find out the change of V/Q distribution curve. After the experiments, the animals were dissected and the lungs were extracted for wet/dry weight ratio (WW/DW) and microscopic examination, Results: In the Toxin group, the pulmonary arterial pressures were increased and arterial oxygen tensions were decreased after the endotoxin infusion. The lung WW/DW were increased and inflammatory findings were seen in microscopic examination. In the MIGET, shunt, deadspace and log SDQ were increased in the toxin group, though there were wide V/Q distributions in the control group. Conclusions: We developed a successful endotoxin induced septic animal model, V/Q distribution curve and data using MIGET. The accomplishment of the experiment will not only allow us to better understand pulmonary pathophysiology of endotoxin induced sepsis using MIGET, but it will also contribute to other pulmonary physiology experiments associated with sepsis. (Korean J Anesthesiol 2001; 40: 655~663)

Bone morphogenetic proteins, genetics and the pathophysiology of primary pulmonary hypertension

Several recent papers have shown that both familial primary pulmonary hypertension (FPPH) and sporadic primary pulmonary hypertension (PPH) may have a common etiology that is associated with the inheritance and/or spontaneous development of germline mutations in the bone morphogenetic protein receptor (BMPR) type II gene. Because BMPR-II is a ubiquitously expressed receptor for a family of secreted growth factors known as the bone morphogenetic proteins (BMPs), these findings suggest that BMPs play an important role in the maintenance of normal pulmonary vascular physiology. In the present commentary we discuss the implications of these findings in the context of BMP receptor biology, and relate these data to the genetics and pulmonary pathophysiology of patients with PPH.

High-frequency oscillatory ventilation in pediatric patients.

High-frequency oscillatory ventilation (HFOV) is a ventilatory mode using small tidal volumes with low phasic pressures at supraphysiological frequencies. Beyond the neonatal period there are distinct lung diseases for which HFOV is used. Data of 35 children who deteriorated on conventional ventilation were retrospectively analysed in two tertiary pediatric intensive care units. Depending on the underlying pulmonary pathophysiology, three strategies were employed. First, the 'open-lung' strategy designed to rapidly recruit and maintain optimal lung volume in DAD (n=27) and pulmonary hemorrhage (n=5). Second, the 'low-volume' strategy in persistent air leak (n=1) where, after an initial identical approach, mean airway pressure (MAP) is reduced until the air leak ceases. Third, the 'open-airway' strategy in obstructive airway disease (n=5) where MAP is used to recruit and stent the airways. Seven patients died, two due to respiratory failure. Three patients developed an air leak. Nine patients developed chronic lung disease. There was a significant decrease of the oxygenation index (OI) in the survivors. In the two patients who died of respiratory failure, the OI increased. If certain conditions are met, HFOV appears a safe and effective mode of ventilation in pediatric respiratory failure.

Receptor- and non-receptor-mediated clearance of bigendothelin and endothelin-1

The aims of this study were to define and characterize the different mechanisms and sites of clearance of plasma endothelin-1 (ET-1) and big endothelin-1 (BigET-1) and evaluate possible effects of ETA versus combined ETA and ETB receptor blockade or endothelin converting enzyme (ECE) inhibition. Time courses and sites of clearance were evaluated in Wistar-Kyoto rats after bolus injection of radiolabelled peptides into the carotid artery before or after treatment with LU1 35252 (ETA) and bosentan (ETA and ETB) as receptor antagonists or the ECE inhibitor phosphoramidon. The study shows that differential clearance of 125I-ET-1 and 125I-BigET-1 is mediated by distinct tissue-specific, receptor- and non-receptor-mediated mechanisms. Low levels of plasma ET-1 are rapidly cleared, mainly in the pulmonary circulation, through a low-capacity saturable ETB receptor-linked mechanism. In contrast, BigET-1 clearance is markedly slower, confined largely to liver and kidneys, is essentially non-receptor-mediated and is independent of converting enzyme activity. Acute inhibition of both ETA and ETB receptors with bosentan dramatically prolonged 125I-ET-1 plasma half-life and shifted tissue uptake from lung to liver and kidneys. Pulmonary clearance of 125I-ET-1 was decreased by chronic but not acute treatment with the specific ETA receptor antagonist LU135252. In contrast, 125I-Big-ET-1 clearance and tissue uptake were essentially unchanged by all treatments. Plasma levels and clearance studies on ET-1 and BigET-1 may provide differential information regarding pathological changes in their separate uptake mechanisms. Such data could have diagnostic or prognostic value in pulmonary, hepatic and renal pathophysiology or future therapeutic monitoring of treatment efficacy following administration of selective receptor antagonists.

Pulmonary expression of iNOS and HO-1 protein is upregulated in a rat model of prehepatic portal hypertension.

Portal hypertension is associated with a wide range of pulmonary pathophysiologies, ranging from portopulmonary hypertension to hepatopulmonary syndrome. Although the clinical and pathological features of pulmonary dysfunction in this setting have been extensively characterized, the underlying biology is not well understood. Specifically, the role of mediators that regulate mesenteric vascular hemodynamics in portal hypertension, such as nitric oxide and endothelin, have not been studied in the lung. Using a rat model of prehepatic portal hypertension with preserved hepatic function, we examined pulmonary elaboration of endothelial nitric oxide synthase (NOS), inducible NOS, heme oxygenase- 1 (HO-1), heme oxygenase-2 (HO-2), endothelin-1 mRNA, and protein. In comparison to sham controls, portal hypertensive animals exhibited significantly increased pulmonary iNOS and HO-1 mRNA and protein. Cyclic GMP was significantly increased in portal hypertensive lung tissue, suggesting activation of guanylyl cyclase by the endproducts of iNOS and/or HO-1 activity. Using immunohistochemical analysis, iNOS expression was localized to the vascular endothelium, while HO-1 localized to bronchiolar epithelium and macrophages. These results suggest that production of nitric oxide and carbon monoxide may contribute to the pulmonary pathology associated with portal hypertension.

Mechanical force-induced signal transduction in lung cells.

The lung is a unique organ in that it is exposed to physical forces derived from breathing, blood flow, and surface tension throughout life. Over the past decade, significant progress has been made at the cellular and molecular levels regarding the mechanisms by which physical forces affect lung morphogenesis, function, and metabolism. With the use of newly developed devices, mechanical forces have been applied to a variety of lung cells including fetal lung cells, adult alveolar epithelial cells, fibroblasts, airway epithelial and smooth muscle cells, pulmonary endothelial and smooth muscle cells, and mesothelial cells. These studies have led to new insights into how cells sense mechanical stimulation, transmit signals intra- and intercellularly, and regulate gene expression at the transcriptional and posttranscriptional levels. These advances have significantly increased our understanding of the process of mechanotransduction in lung cells. Further investigation in this exciting research field will facilitate our understanding of pulmonary physiology and pathophysiology at the cellular and molecular levels.

Pathophysiological effect of fat embolism in a canine model of pulmonary contusion.

The objective of this study was to determine the individual and combined effects of pulmonary contusion and fat embolism on the hemodynamics and pulmonary pathophysiology in a canine model of acute traumatic pulmonary injury. After a thoracotomy, twenty-one skeletally mature dogs were randomly assigned to one of three groups. Unilateral pulmonary contusion alone was produced in Group 1 (seven dogs); pulmonary contusion and fat embolism, in Group 2 (seven dogs); and fat embolism alone, in Group 3 (seven dogs). Pulmonary contusion was produced by standardized compression of the left lung with a piezoelectric force transducer. Fat embolism was produced by femoral and tibial reaming followed by pressurization of the intramedullary canals. Cardiac output, systolic blood pressure, peak airway pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, partial pressure of arterial oxygen, and partial pressure of carbon dioxide were monitored for all groups. From these data, several outcome parameters were calculated: total thoracic compliance, alveolar-arterial oxygen gradient, and ratio of partial pressure of arterial oxygen to fractional inspired oxygen concentration. All of the dogs were killed after eight hours, and tissue samples were obtained from the brain, kidneys, and lungs for histological analysis. Lung samples were assigned scores for pulmonary edema (the presence of fluid in the alveoli) and inflammation (the presence of neutrophils or hyaline membranes, or both). The percentage of the total area occupied by fat was determined. Pulmonary contusion alone caused a significant increase in the alveolar-arterial oxygen gradient but only after seven hours (p = 0.034). Fat embolism alone caused a significant transient decrease in systolic blood pressure (p = 0.001) and a significant transient increase in pulmonary arterial pressure (p = 0.01) and pulmonary capillary wedge pressure (p = 0.015). Fat embolism alone also caused a significant sustained decrease in the ratio of partial pressure of arterial oxygen to fractional inspired oxygen concentration (p = 0.0001) and a significant increase in the alveolar-arterial oxygen gradient (p = 0.0001). The combination of pulmonary contusion and fat embolism caused a significant transient increase in pulmonary capillary wedge pressure (p = 0.0013) as well as a significant sustained decrease in partial pressure of arterial oxygen (p = 0.0001) and a significant decrease in systolic blood pressure (p = 0.001) that lasted for an hour. Pulmonary contusion followed by fat embolism caused a significant increase in peak airway pressure (p = 0.015), alveolar-arterial oxygen gradient (p = 0.0001), and pulmonary arterial pressure (p = 0.01), and these effects persisted for five hours. Total thoracic compliance was decreased 6.4 percent by pulmonary contusion alone, 4.6 percent by fat embolism alone, and 23.5 percent by pulmonary contusion followed by fat embolism. The ratio of partial pressure of arterial oxygen to fractional inspired oxygen concentration was decreased 23.7 percent by pulmonary contusion alone, 52.3 percent by fat embolism alone, and 65.8 percent by pulmonary contusion followed by fat embolism. The mean pulmonary edema score was significantly higher with the combined injury than with either injury alone (p = 0.0001). None of the samples from the lungs demonstrated inflammation. Fat embolism combined with pulmonary contusion resulted in a significantly greater mean percentage of the area occupied by fat in the noncontused right lung than in the contused left lung (p = 0.001); however, no significant difference between the right and left lungs could be detected with fat embolism alone. The mean percentage of the glomerular and cerebral areas occupied by fat was greater with fat embolism combined with pulmonary contusion than with fat embolism alone (p = 0.0001 and p = 0.01, respectively). (ABSTRACT TRUNCATED)

Neuroepithelial bodies as airway oxygen sensors

Since the discovery of neuroepithelial bodies (NEB) in the late 1930s, evidence has accumulated to suggest that these cells may function as hypoxia-sensitive airway sensors. Until recently, this hypothesis was based largely on morphological observations. The use of in vitro models of isolated NEB, combined with electrophysiological approaches, have provided direct evidence that NEB cells express a membrane-bound O 2 sensor and are the transducers of hypoxic stimulus. Here, we review the historical evidence and current state of knowledge of the oxygen-sensing properties of NEB cells, comparison with other O 2 sensing cells, as well as recent advances that have been made using molecular and electrophysiological techniques. The possible role of NEB in perinatal pulmonary pathophysiology is also discussed.

Inflammation and CFTR: might neutrophils be the key in cystic fibrosis?

The aim of this hypothesis is to provide new insights into the still unclear mechanisms governing airway inflammation in cystic fibrosis. Although the genetic basis of cystic fibrosis as well as the molecular structure of cystic fibrosis transmembrane regulator (CFTR), the mutated protein which causes the disease, have been well defined, a clear relationship between the genetic defect and the pulmonary pathophysiology, especially chronic infections and neutrophil-dominated airway inflammation has not been established. Cystic fibrosis is thus a unique pathological situation in that neutrophils can be depicted as both an antiinfectious and a proinflammatory cell. In cystic fibrosis there is an emerging picture of an imbalance between these two roles with both a reduction in the antiinfectious efficacy and an augmentation of the proinflammatory functions. Better knowledge of fundamental defects in neutrophil function in cystic fibrosis as well as a novel cellular function of CFTR, which will be reviewed, will allow identification of potentially new clinical targets and aid selective therapeutic action aimed at counteracting the lethal neutrophil-induced airway inflammation. The rationale for colchicine therapy is a significant example of a drug which might act both at the molecular levels on CFTR expression in epithelial cells and on neutrophils to mediate antiinflammatory effects. Preliminary results are presented in this issue (Med Inflamm 1999; 8: 13-15).

Pulmonary Pathophysiology: The Essentials, 5th Edition

Pulmonary Pathophysiology: The Essentials, 5th Edition

Fill-in after reinjection of Tc-99m MAA.

Combined pulmonary ventilation/perfusion (V/P) scintigraphy for assessing and monitoring pulmonary pathophysiology should be performed so that perfusion information exactly corresponding to ventilation can be obtained. An area of impaired V/P was shown in the affected lung of a patient with pneumothorax by combined pulmonary V/P scintigraphy. Additional combined pulmonary V/P scintigraphy following reinjection of Tc-99m MAA on a single maximal inspiration demonstrated improvement in both perfusion and ventilation The findings represent well-known pathophysiology. Hypoventilation causes reflex vasoconstriction of the pulmonary artery and when ventilation improves, so does perfusion. This suggests that a perfusion abnormality improved following pneumothorax.

Accurate measurement of intrathoracic airways.

Airway geometry measurements can provide information regarding pulmonary physiology and pathophysiology. There has been considerable interest in measuring intrathoracic airways in two-dimensional (2-D) slices from volumetric X-ray computed tomography (CT). Such measurements can be used to evaluate and track the progression of diseases affecting the airways. A popular airway measurement method uses the "half-max" criteria, in which the gray level at the airway wall is estimated to be halfway between the minimum and maximum gray levels along a ray crossing the edge. However, because the scanning process introduces blurring, the half-max approach may not be applicable across all airway sizes. We propose a new measurement method based on a model of the scanning process. In our approach, we examine the gray-level profile of a ray crossing the airway wall and use a maximum-likelihood method to estimate the airway inner and outer radius. Using CT scans of a physical phantom, we present results showing that the new approach is more accurate than the half-max method at estimating wall location for thin-walled airways.